Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond.

摘要: Cells have a number of mechanisms to maintain protein homeostasis, including proteasome-mediated degradation ubiquitinated proteins and autophagy, regulated process “self-eating” where the contents entire organelles can be recycled for other uses. The unfolded response prevents overload in secretory pathway. In past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory complexes such as NLRP3 inflammasome. Signaling pathways UPR co-opted by toll-like receptor mitochondrial reactive oxygen species signaling induce inflammatory responses. Mutations alter key proteins, or TNFR1, overcome normal homeostasis mechanisms, resulting autoinflammatory diseases. Conversely, Mendelian defects proteasome cause accumulation, which trigger interferon-dependent disease. non-Mendelian diseases, polymorphisms genes affecting autophagy contribute disease, diseases not formerly considered neurodegenerative conditions type 2 diabetes, there is increasing evidence cell intrinsic environmental alterations may pathogenesis.